Aptamers are single-stranded oligonucleotides which are able to bind with high affinity to specific protein or non-protein targets by folding into complex tertiary structures. Aptamers have generally proven useful as reagents for identifying cell surface proteins and for cell typing. Furthermore, their high specificity and low toxicity render them a valid alternative to antibodies for in vivo targeted recognition as therapeutics or delivery agents for nanoparticles, small interfering RNAs, chemotherapeutics and molecular imaging probes.
The platelet-derived growth factor receptor (PDGFR) is an important member of receptor tyrosine kinase (RTK) family. Its ligand, PDGF, has a wide array of important effects on mitogenesis, migration, and development.
More specifically, platelet-derived growth factors (PDGFs) are a family of potent mitogens for almost all mesenchyme-derived cells. The PDGF family consists of four polypeptides, A-D, forming five disulfide-linked dimeric proteins PDGF-AA, -BB, -AB, -CC, and -DD that signal through two structurally similar tyrosine kinase receptors, platelet-derived growth factor receptors α and β (PDGFRα and PDGFRβ). The ligands and receptors can form homodimers or heterodimers depending on cell type, receptor expression, and ligand availability. PDGF-BB and PDGF-DD are the primary activators of ββ homodimeric receptors. PDGF-AA activates only αα receptor dimers, whereas PDGF-AB, PDGF-BB, and PDGF-CC activate αα and αβ receptor dimers (Yarden Y et al., 1986; Matsui T et al., 1989). PDGF receptors have been extensively studied regarding their signaling mechanism, in particular PDGFRβ. The dimeric ligand molecules bind to two receptor proteins simultaneously and induce receptor dimerization, autophosphorylation of specific residues within the receptor's cytoplasmic domain, and intracellular signaling. It has been demonstrated that the activation of PDGFRβ signaling pathway induces various cellular responses, including cell proliferation, migration and angiogenesis (Andrae et al., 2008; Ustach et al., 2010; Cao et al., 2004).
In embryogenesis the PDGFR/PDGF system is essential for the correct development of the kidney, cardiovascular system, brain, lung and connective tissue (Betsholtz et al., 2001; Hoch et al., 2003). In adults, it is important in wound healing, inflammation and angiogenesis. Abnormalities of PDGFR/PDGF are thought to contribute to a number of human diseases including cancer. Overexpression, point mutations, deletions and translocations of PDGFR, including PDGFRβ, have been described in many tumors (Gilbertson et al., 2003; Yu et al., 2003; George, 2003).
Furthermore, preclinical studies have not only shown an important role for the overexpression and deregulated activation of PDGFRβ-mediated signaling in tumorigenesis and the maintenance of the malignant phenotype, but have also proven that the targeted inhibition of signaling cascades has significant anti-cancer effects (Vassbotn et al., 1993; Kilic et al., 2000; Shamah et al., 1993). Overall these data indicate that PDGFRβ represents a valuable target for tumor therapeutic development (George, 2003).
A number of tyrosine kinase inhibitors under development as anti-tumor agents have been found to inhibit the PDGFRβ. However, these compounds are not selective and have multiple tyrosine kinase targets. Since these small molecule antagonists are not specific to this receptor, it is not possible to distinguish the contribution of PDGFRβ signaling to cancer, including tumor-associated angiogenesis, tumor stimulation and growth, or toxicities associated with administration of such compounds that might be due to unnecessary targeting of multiple receptors.
Among the small molecular inhibitors of PDGFR that act on a wide spectrum of tyrosine protein kinases, imatinib mesylate (Gleevec®/ST571) was developed as an Abelson (Abl) tyrosine kinase inhibitor, and also inhibits c-kit, PDGFRα, and PDGFRβ. Sunitinib malate (Sutent®/SU11248) is a broad-spectrum, orally available multitargeted tyrosine kinase inhibitor with activity against VEGFR, PDGFR, c-KIT, and FLT-3. CP-673,451 is an inhibitor of both PDGFRα and PDGFRβ. Sorafenib (Nexavar®) is an inhibitor of Ras/Raf/MEK/ERK pathway and of angiogenic RTKs VEGFR2 and PDGFRβ. However, toxicity is associated with administration of such compounds that might be due to unnecessary targeting of multiple receptors.
Neutralizing antibodies exist for PDGF ligands and receptors and have been used extensively in experiments evaluating the importance of PDGF signaling in pathogenic processes but, to date, no antibodies exist in clinic (Johanna et al., 2008).
Thus, there is the urgent need to provide a new PDGFRβ-targeting drug for a more specific and selective tumour therapy.